Microglial homeostasis requires balanced CSF-1/CSF-2 receptor signaling

ALSP is a CSF1R-deficiency dementia associated with increased CSF2 expression Monoallelic deletion of Csf2 rescues most behavioral deficits and histopathological changes in Csf1r+/- mice by preventing microgliosis and eliminating most microglial transcriptomic alterations, including those indicative of oxidative stress and demyelination Elevation of Csf2 transcripts and of several CSF-2 downstream targets in the brains of ALSP patients demonstrates that the mechanisms identified in the mouse model are functional in man. Our data provide new insights into the mechanisms underlying ALSP and identify CSF-2 as a therapeutic target. Overall design: Examination of the effect of single or double Csf1r and Csf2 heterozygosity on behavior, brain histopathology and microglial transcriptomic profiles.